Purinergic Signaling Differentially Modulates Normal and Leukemic Hematopoiesis.

Abstract 1436

Poster Board I-459

Extracellular nucleotides adenosine and uridine triphosphates (ATP and UTP, respectively) are emerging as ubiquitous molecules involved in a wide variety of biological responses and their biological effects are mediated by specific plasma membrane receptors, P2 receptors (P2R). Previously, we showed that extracellular nucleotides stimulate the proliferation and engraftment potential of normal human hematopoietic stem cells. In this study, we assessed whether P2R are expressed on acute myeloblastic leukemia (AML) cells and whether their engagement modulates leukemic cell functions. We show that AML cells express several functional P2R subtypes at the molecular and protein level. Stimulation of AML cells by extracellular nucleotides induced intracellular Ca²⁺ concentration increases. Furthermore, gene expression profiling revealed that leukemic cells stimulated with ATP underwent a down-regulation of genes involved in cell proliferation and migration whereas those involved in cell cycle inhibition were strongly up-regulated. At the functional level, the clonogenic efficiency of leukemic blasts and CD34⁺CD38⁻ leukemic stem/progenitor cells was significantly inhibited by the addition of ATP and, to a higher extent, by the stable analogs INS415 and INS973. We also observed a pronounced inhibitory effect of triphosphate nucleotides on spontaneous migration of AML cells and in response to CXCL12.In vivo, xenotransplant experiments demonstrated that the homing and the engraftment capacity of human AML blasts and leukemic stem cells to NOD/SCID/IL-2RGamma-Null mice was significantly inhibited by pre-treatment with ATP, UTP and INS415 and INS973 analogues. Thus, our data show that purinergic signaling modulates leukemic cells in a opposite way than normal cells. Characterization of purinergic signalling in leukemia may help the better understading of the mechanism of neoplastic transformation and tumor progression.